Non-isosmotic diafiltration system

ABSTRACT

A method of hemodiafiltration including the steps of supplying a blood inflow, diafiltering the blood inflow using a first non-isosmotic dialysate fluid to provide a partially diafiltered blood outflow, mixing the partially diafiltered blood outflow with a substitution fluid to provide a blood/substitution fluid mixture, and diafiltering the blood/substitution fluid mixture using a second non-isosmotic dialysate fluid.

This application claims the benefit of provisional application60/106,322 filed Oct. 30, 1998.

FIELD OF THE INVENTION

The present invention relates to blood cleansing in general and, moreparticularly, to diafiltration systems.

BACKGROUND OF THE INVENTION

Hemodiafiltration combines standard dialysis and hemofiltration into oneprocess, whereby a dialyzer cartridge containing a high flux membrane isused to remove substances from the blood both by diffusion and byconvection. The removal of substances by diffusion is accomplished byestablishing a concentration gradient across a semi-permeable membraneby flowing a dialysate solution on one side of the membrane whilesimultaneously flowing blood on the opposite side of the membrane. Toenhance removal of substances using hemodiafiltration, a substitutionfluid is continuously added to the blood either prior to the dialyzercartridge (pre-dilution) or after the dialyzer cartridge(post-dilution). An amount equal to that of the substitution fluid isthen ultrafiltered across the dialyzer cartridge membrane carrying withit additional solutes.

Substitution fluid is usually purchased as a sterile/non-pyrogenic fluidcontained in large flexible bags or is produced by on-line filtration ofa non-sterile dialysate through a suitable filter cartridge rendering itsterile and non-pyrogenic. Such on-line production of substitution fluidis described, inter alia, in D. Limido et al., “Clinical Evaluation ofAK-100 ULTRA for Predilution HF with On-Line Prepared BicarbonateSubstitution Fluid. Comparison with HD and Acetate Postdilution HF”,International Journal of Artificial Organs, Vol. 20, No.3 (1997), pp.153-157.

In general, hemodiafiltration schemes use a single dialyzer cartridgecontaining a high flux semi-permeable membrane. Such a scheme isdescribed, for example, in P. Ahrenholz et al., “On-LineHemodiafiltration with Pre- and Postdilution: A comparison ofEfficiency”, International Journal of Artificial Organs, Vol. 20, No.2(1997), pp 81-90 (“Ahrenholz et al.”). Substitution fluid is introducedinto the blood stream either in a pre-dilution mode or in apost-dilution mode relative to the dialyzer cartridge. The preferredmode for maximal removal of both small and large substances from bloodis the post-dilution mode, which achieves the highest concentrationgradient between the blood and the dialysate fluid. In a typicalpre-dilution mode with on-line generation of the substitution fluid,however, the bloodside concentration is lowered relative to thedialysate fluid. As a result, removal (or clearance) of substances candecrease, as described in Ahrenholz et al. This is particularly true forsmaller molecules like urea, whereby mass transport is driven more bythe diffusion process than by the convection process.

A hemodiafiltration scheme using first and second dialyzer cartridges isdescribed in J. H. Miller et al., “Technical Aspects of High-FluxHemodiafiltration for Adequate Short (Under 2 Hours) Treatment”,Transactions of American Society of Artificial Internal Organs (1984),pp. 377-380. In this scheme, the substitution fluid is reverse-filteredthrough a membrane of the second dialyzer cartridge with simultaneousfiltration of fluid across a membrane in the first dialyzer cartridge.Counter-current flow of dialysate occurs at both cartridges.

Certain trade-offs exist with respect to removal of different sizemolecules when comparing pre-dilution diafiltration and post-dilutiondiafiltration using a single dialyzer cartridge. For example, withon-line pre-dilution diafiltration, one can achieve higher convectivefiltration rates (compared to on-line post-dilution diafiltration) toenhance removal of large molecules, however, this comes at the expenseof reducing the removal of small molecules like urea and creatinine. Inon-line post-dilution diafiltration, however, only a limited amount offluid can be filtered from the blood as it passes through the dialyzercartridge. The filterable amount is dependent upon several factors,including blood flow rate, blood hematocrit and blood proteinconcentration. Typically, the filterable amount is 20% to 30% of theincoming blood flow, depending on blood flow rate. For example, at ablood flow rate of 300 ml/min, the filterable amount is limited to about90 ml/min. Additionally, in on-line pre-dilution or post-dilutiondiafiltration, there is some loss in clearance due to the lowerdialysate flow rate through the diafilter cartridge. For example, at anominal dialysate flow of 500 ml/min, when 100 ml/min is used as anon-line source of substitution fluid, the resultant dialysate flow intothe diafilter cartridge is 400 ml/min.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a hemodiafiltrationmethod and a device which overcome the limitations associated withconvection filtration in existing on-line post-dilution schemes. It isalso an object of the present invention to reduce the loss of smallmolecule clearance associated with on-line pre-dilution diafiltrationusing a single dialyzer cartridge. In accordance with the presentinvention, clearance is improved by introducing a non-isosmotic fluid tothe dialysate fluid stream and optionally to the substitution fluidstream.

The present invention may be embodied in an improved dialysis machine,e.g., a dialysis machine which is adapted to perform improvedhemodiafiltration in accordance with the invention. Alternatively, thehemodiafiltration device of the present invention may be embodied in an“add-on” system which may be used in conjunction with a standard UFcontrolled dialysis machine to perform improved hemodiafiltration.

A hemodiafiltration device in accordance with an embodiment of thepresent invention includes at least one dialyzer (e.g., a dialyzercartridge) for diafiltration, at least one sterility filter (e.g., asterility filter cartridge) for generating a sterile substitution fluid,a non-isosmotic fluid supply, and a control unit which controls fluidinputs and outputs between the at least one dialyzer, the at least onesterility filter cartridge, the non-isosmotic fluid supply and thedialysis machine.

The dialyzer may contain a semi-permeable membrane which may be embeddedwithin a jacket or housing of a dialyzer cartridge. The membraneseparates the dialyzer into a blood compartment and a dialysatecompartment. In an embodiment of the present invention, at least firstand second dialyzers are used to carry out the diafiltration process.The first and second dialyzers may include first and second dialyzercartridges or a single cartridge having first and second dialyzersections. The at least one sterility filter may contain semi-permeablemembranes and may be used to remove bacteria, endotoxins, and otherparticulate from the dialysate, thereby generating a suitablesubstitution fluid stream on-line. The control unit may contain variouspumps, pressure monitoring devices, valves, electronic components,connector fittings, tubing, etc., as required in order to coordinate theoperation of the other system components.

Blood enters the bloodside compartment of the first dialyzer, wherebysome plasma water is filtered across the semi-permeable membrane intothe adjacent dialysate compartment. As the blood leaves the firstdialyzer, substitution fluid is added to the blood at a rate higher thanthe rate at which plasma water is filtered out of the first dialyzer. Inaccordance with an embodiment of the present invention, the substitutionfluid may include a non-isosmotic substitution fluid.

The diluted blood then enters the bloodside compartment of the seconddialyzer, whereby additional plasma water (equal to the excess amount ofsubstitution fluid) is filtered across the semi-permeable membrane andinto the adjacent dialysate compartment. In this manner, thesubstitution fluid acts as a post-dilution fluid relative to the firstdialyzer as well as a pre-dilution fluid relative to the seconddialyzer.

An advantage of this process is that a gain in clearance of smallmolecular weight substances in the first dialyzer overshadows a loss inclearance of small molecular weight substances due to the dilution ofblood concentration entering the second dialyzer. Further, clearance oflarger molecular weight substances is enhanced considerably, because thetotal filtration level of plasma water is practically doubled (e.g. 40%to 80% of the incoming blood flow rate may be filtered) compared tofiltration using a single dialyzer operating in a post-dilution mode.

The dialysate fluid may be generated by the dialysis machine.Preparation of the dialysate solution may include mixing of water withdialysate concentrate. Using a water preparation module, a supply ofwater may be pre-treated, e.g., by heating and/or degassing or using anyother pre-treatment method known in the art. A dialysate preparationmodule, as is known in the art, may be used to supply dialysateconcentrate to obtain suitable proportioning of dialysate to water.

When two dialyzers are used, the dialysate fluid may enter the seconddialyzer cartridge and run counter-parallel to the blood flow direction.In accordance with an embodiment of the present invention, the dialysatepreparation module produces non-isosmotic or isosmotic dialysate fluid.The dialysate fluid acts to provide a concentration gradient against thebloodside fluid thereby facilitating the diffusion of solutes across thesemi-permeable membrane. As the dialysate traverses through thedialysate compartment, the dialysate flow rate increases due to plasmawater filtering across into the dialysate compartment as mentionedabove. Upon exiting the second dialyzer cartridge, the dialysate fluidmay be pumped into the first dialyzer cartridge, again runningcounter-parallel to the bloodside fluid. At this point, a non-isosmoticdialysate fluid may be added to the dialysate fluid, resulting in fluidwhich is either hypertonic or hypotonic relative to the blood. Theaddition of this fluid may have the following effects: (a) an increasein the overall dialysate flow results in a reduction of the dialysateside-mass transport resistance; (b) a reduction in the dialysate inletsolute concentration prior to entering the first dialyzer cartridgeresults in an increase of the concentration gradient across thesemi-permeable membrane; (c) a fluid shift across the red blood cellmembrane further enhances transport of solutes out of the red bloodcells; and (d) larger molecules sieved by the red blood cell membraneare trapped in the plasma water space thus increasing theirconcentration gradient relative to the dialysate. In some embodiments ofthe invention, pre-treated water is used as the non-isosmotic fluidadded to the dialysate fluid. This may have the added benefit ofincreasing dialysate flow without increasing costs associated with theamount of dialysate concentrate being used.

The dialysate flow rate increases as it traverses through the dialysatecompartment again, due to filtration of plasma water across thesemi-permeable membrane. Upon exiting the dialyzer cartridges, the useddialysate is transported back to the dialysis machine. A dialysate pumpmay be placed between the first and second dialyzers. The pump may beused to control the relative amount of plasma water filtered across themembranes of the two dialyzers.

Preparation of the sterile/non-pyrogenic substitution fluid may beperformed by drawing a portion of fresh dialysate solution from adialysate inlet line and pumping it through the sterile filtercartridge. Water from the water preparation module may be added to thedialysate, such that the substitution fluid becomes hypotonic before itis infused into the blood stream. The sterile filter cartridge mayperform multiple filtration of the dialysate solution, e.g., using aplurality of filtration cartridges or a plurality of filtration sectionsin a single cartridge, before introducing the dialysate into the bloodstream as substitution fluid. This enhances safety, e.g., should one ofthe filters fail during treatment.

To ensure that the blood does not become diluted or over-concentrated asit passes through the dialyzer cartridges, control of filtration may beaccomplished by use of two independent fluid balancing systems and aseparate UF pump. A main balance system may regulate the overalldialysate flows, while a secondary balance system may be used to balancedialysate flows that are offset by the addition of a second fluid streamto the dialysate circuit as part of the non-isosmotic flow streams. Toensure that the blood being cleaned returns substantially to itsoriginal osmotic state before going back to the patient, the primarydialysate fluid may be isotonic, slightly hypertonic, or slightlyhypotonic, depending on the nature of the second dialysate fluid.Pressures may be monitored both on the bloodside and dialysate side ofeach dialyzer cartridge as a means to determine transmembrane pressure(TMP) across each of the dialyzers.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be understood and appreciated more fully fromthe following detailed description of embodiments of the presentinvention, taken in conjunction with the accompanying drawing in which:

FIG. 1A is a schematic illustration of a first section of anon-isosmotic hemodiafiltration device system in accordance with anembodiment;

FIG. 1B is a schematic illustration of a second section of anon-isosmotic hemodiafiltration system in accordance with an embodiment;and

FIG. 2 is a schematic illustration of a control unit for monitoring andcontrolling the operation of the hemodiafiltration system of FIG. 1 inaccordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The hemodiafiltration method and device of the present invention will bedescribed below in the context of a stand-alonedialysis/hemodiafiltration machine. It should be appreciated, however,that the hemodiafiltration method and device of the present inventioncan also be embodied in an add-on type system used in conjunction withan existing UF controlled dialysis machine.

In an embodiment of the present invention, as described below withreference to the drawing, the hemodiafiltration device includes firstand second dialyzer cartridges. Alternatively, a single cartridge havingfirst and second, separate, dialyzer sections may be used.

The hemodiafiltration device further includes at least one sterilityfilter, which may contain semi-permeable membranes for removingbacteria, endotoxins, and other particulate from the dialysate, therebyto generate a suitable substitution fluid stream on-line. The devicealso includes a fluid module to coordinate between different elements ofthe system. The fluid module contains various pumps, pressure monitoringdevices, valves, electronic components, connector fittings, tubing,etc., as required in order to coordinate the operation of the othersystem components.

In accordance with an embodiment of the present invention, preparationof dialysate solution includes mixing of water with dialysateconcentrate. Using a water preparation module, a supply of water may bepre-treated, e.g., by heating and/or degassing or using any otherpre-treatment method known in the art. A dialysate preparation modulemay be used to supply a predetermined amount of dialysate concentrate toobtain a suitable proportioning of dialysate to water.

When two dialyzers are used, the dialysate fluid may enter the seconddialyzer cartridge and run counter-parallel to the blood flow direction.In accordance with an embodiment of the present invention, the dialysatepreparation module produces non-isosmotic dialysate fluid. The dialysatefluid acts to provide a concentration gradient against the bloodsidefluid thereby facilitating the diffusion of solutes across thesemi-permeable membrane. As the dialysate traverses through thedialysate compartment, the dialysate flow rate increases due to plasmawater filtering across into the dialysate compartment as mentionedabove. Upon exiting the second dialyzer cartridge, the dialysate fluidmay be pumped into the first dialyzer cartridge, again runningcounter-parallel to the bloodside fluid. At this point, a non-isosmoticdialysate fluid may be added to the dialysate fluid, resulting in fluidwhich is either hypertonic or hypotonic relative to the blood. Theaddition of non-isosmotic fluid to the dialysate fluid may have thefollowing effects: (a) an increase in the overall dialysate flow resultsin a reduction of the dialysate side-mass transport resistance; (b) areduction in the dialysate inlet solute concentration prior to enteringthe first dialyzer cartridge results in an increase of the concentrationgradient across the semi-permeable membrane; (c) a fluid shift acrossthe red blood cell membrane further enhances transport of solutes out ofthe red blood cells; and (d) larger molecules sieved by the red bloodcell membrane are trapped in the plasma water space thus increasingtheir concentration gradient relative to the dialysate. In an embodimentof the invention, pretreated water is used as the non-isosmotic fluidadded to the dialysate fluid. This may have the added benefit ofincreasing dialysate flow without increasing costs associated with theamount of dialysate concentrate being used.

A sterile/non-pyrogenic substitution fluid for use in conjunction withthe present invention may be prepared by drawing a portion of freshdialysate solution from a dialysate inlet line and pumping it through asterile filter cartridge. In an embodiment of the present invention, thesterile filter cartridge performs at least a double filtration of thedialysate solution before the solution is introduced into the bloodstream as a substitution fluid. This double filtration can be performedby two separate ultrafiltration filter cartridges or a single cartridgethat has multiple sections to perform multiple filtration of thesubstitution fluid. The use of multiple filtration to generate theon-line substitution fluid makes the system of the present inventionsafer, should one of the filters fail during treatment.

The dialysis machine used in conjunction with the present invention mayperform all of its normal functions, such as metering dialysate flowrate, monitoring pressures, controlling net ultrafiltration, monitoringused dialysate for blood presence, etc. The hemodiafiltration device ofthe present invention operates in conjunction with the dialysis machine,either as part of the dialysis machine or as an add-on system, e.g., tore-distribute dialysate fluid to its respective dialyzer and sterilefilter cartridges. Preparation of non-isosmotic dialysate fluid, asdescribed in detail below, may be performed by a preparation moduleincluded in the dialysis machine. The fluid handling components of thehemodiafiltration system may be integrated with a microprocessor unitfor controlling and executing the diafiltration aspect of the treatment,or a control unit of the dialysis machine may be adapted to control thehemodiafiltration aspects of the treatment.

Reference is now made to the FIG. 1, which schematically illustrates anon-isosmotic hemodiafiltration device in accordance with an embodimentof the present invention. It should be appreciated that the system ofFIG. 1 demonstrates only one preferred embodiment of the invention, andthat other possible configurations of the system of the presentinvention may be equally or even more suitable, depending on specificrequirements. For example, the use of a substantially hypotonicdialysate fluid in the first dialyzer stage and a substantiallyhypertonic dialysate fluid in the second dialyzer stage, as describedbelow, may be reversed in some embodiments of the invention, i.e., asubstantially hypertonic dialysate fluid may be used in the firstdialyzer stage and a substantially hypotonic dialysate fluid may be usedin the second dialyzer stage.

In the system of FIG. 1, blood to be cleaned 27 enters a first dialyzercartridge 23 after passing through blood monitoring devices 137 and 26.Blood monitoring devices 137 and 26 monitor the incoming blood pressureand/or the incoming blood flow rate and provide an input, responsive tothe monitored rate, to a control unit 40. The blood is carried bysuitable tubing, as is known in the art, for example, bloodline tubingmade from flexible polyvinylchloride (PVC). The flow rate of incomingblood is generally in the range of 100 to 600 ml/min, preferably 200 to500 ml/min.

First dialyzer cartridge 23 contains a semi-permeable membrane 24 thatdivides the dialyzer into a blood compartment 45 and a dialysatecompartment 46. As blood 27 passes through blood compartment 45, plasmawater containing blood substances is filtered across semi-permeablemembrane 24. Additional blood substances are also transferred acrosssemi-permeable membrane 24 by diffusion due to a difference inconcentration between blood compartment 45 and dialysate compartment 46.

The dialyzer cartridge may be of any type suitable for hemodialysis,hemodiafiltration, hemofiltration, or hemoconcentration, for example,the Fresenius F60, available from Fresenius Medical Care, Lexington,Mass., the Baxter CT 110, available from Baxter Health Care, Deerfield,Ill., the Minntech Hemocor HPH 1000, available from MinntechCorporation, Minneapolis, Minn., or the Hospal Filtral 16, availablefrom Hospal A.G., Switzerland. Membrane 24 is preferably a medium tohigh flux membrane, for example, the polysulfone, cellulose triacetateor acrylonitrile membranes available from Fresenius Medical Care,Lexington, Mass., Minntech Corporation, Minneapolis, Minn., BaxterHealth Care, Deerfield, Ill., or Hospal A.G., Switzerland.

Partially diafiltered blood (denoted 18) exiting dialyzer cartridge 23is mixed with sterile substitution fluid 16 to form a blood/substitutionfluid mixture 17. This mixture enters a second dialyzer cartridge 22containing a semi-permeable membrane 25 which divides the dialyzercartridge 22 into a blood compartment 47 and a dialysate compartment 48.As mixture 17 passes through blood compartment 47, plasma watercontaining blood substances is filtered across the semi-permeablemembrane. As in the first dialyzer cartridge, additional bloodsubstances are transferred across semi-permeable membrane 25 bydiffusion due to concentration gradients between the blood and dialysatecompartments. Cleansed blood 28 exits second dialyzer cartridge 22 andis recycled to the patient (not shown) through suitable tubing, forexample, bloodline PVC tubing, as is known in the art. The pressure ofcleansed blood 28 may also be monitored by a pressure sensor 136.

The second dialyzer cartridge may be of any type suitable forhemodialysis, hemodiafiltration, hemofiltration, or hemoconcentration,for example, the Fresenius F60, available from Fresenius Medical Care,Lexington, Mass., the Baxter CT 110, available from Baxter Health Care,Deerfield, Ill., the Minntech Hemocor HPH 400, available from MinntechCorporation, Minneapolis, Minn., or the Hospal Filtral 16, availablefrom Hospal A.G., Switzerland. Membrane 25 is preferably a medium orhigh flux membrane, for example, the polysulfone, cellulose triacetateor acrylonitrile membranes mentioned above with reference to membrane24.

In accordance with an embodiment of the present invention, the dialysatesolution used for the present invention may be prepared as follows. Asuitable quality of water, such as reverse osmosis water as is known inthe art, is provided from a water source 150. The water enters a waterpreparation module 151 that heats and degasses the water being used bythe hemodiafiltration system. Any suitable heating and degassing moduleas is known in the art may be used in conjunction with the presentinvention. Examples of such modules are included in the followingsystems: the Baxter SPS1550, available from Baxter Health Care,Deerfield, Ill.; the Cobe Centry System 3, available from Cobe Labs,Lakewood, Colo.; the Fresenius A2008, available from Fresenius MedicalCare, Lexington, Mass.; and the Althin System 1000, available fromAlthin Medical, Miami, Fla. The degassed, heated water feeds into twowater supply lines, namely, water feed lines 152 and 153.

Feed line 153 supplies water to prepare a non-isosmotic substitutionfluid in accordance with the present invention, as described below,and/or to increase the flow of dialysate into first dialyzer cartridge23. Feed line 152 supplies water to a dialysate preparation module 154.In dialysate preparation module 154, water is mixed with suitableamounts of dialysate concentrates. Any suitable dialysate preparationmodule as is known in the art may be used in conjunction with thepresent invention. Examples of such modules are included in thefollowing systems: the Baxter SPS1550, available from Baxter HealthCare, Deerfield, Ill.; the Cobe Centry System 3, available from CobeLabs, Lakewood, Colo.; the Fresenius A2008, available from FreseniusMedical Care, Lexington, Mass.; and the Althin System 1000, availablefrom Althin Medical, Miami, Fla. The mixed dialysate fluid exitingdialysate preparation module 154 flows through a conduit 157 leading toa primary dialysate balancing module 158, which may include a fluidbalancing chamber as is known in the art. Primary balancing module 158regulates flow in the sense that flow into balancing module 158 is equalto flow out of the balancing module. This provides initial filtrationcontrol which prevents the blood from becoming over-diluted orover-concentrated when exiting dialyzer cartridge 22. Upon exitingprimary balancing module 158, the dialysate fluid flows via conduit 41to a connector 39 which connects the fluid flow to a dialysate port 1 ofcompartment 48 of second dialyzer cartridge 22.

In an embodiment of the present invention, preparation of a sterilesubstitution fluid is performed by filtration of a dialysate across atleast two filter membranes with a molecular weight cut-off of not morethan 40,000 Daltons. In some embodiments, the nominal molecular weightcut-off for the second filter or final filter (when more than twofilters are used) is not more than 10,000 Daltons, preferably not morethan 5,000 Daltons. To accomplish this, a portion of the fresh dialysatesolution may be split off the dialysate fluid stream at some point priorto entering dialysate compartment 48 of second dialyzer cartridge 22.The split-off portion of the dialysate solution may flow through aconduit 2 leading to a substitution pump 8. Flow rate and pre-pumppressure in conduit 2 may be monitored by a flow meter 10 and a pressuretransducer 9. Substitution fluid pump 8 generates the needed pressure toforce the fluid down a conduit 12, across first and second sterilefilter cartridges, 11 and 13, respectively, and into blood stream 18. Enroute to sterile filters 11 and 13, post-pump pressure and temperaturemay be monitored by a pressure transducer 132 and a temperature sensor133.

To change the osmolality of the substitution fluid, water from a conduit178 may be added to the substitution fluid at some point downstream ofsubstitution fluid pump 8. The resultant osmolality of the substitutionfluid is a function of the relative flow rates of substitution fluidpump 8 and a pump 163 which may be provided along water conduit 178. Themixed substitution fluid stream may be monitored for conductivity by aconductivity meter 187. If the conductivity is determined to be outsidea pre-determined range, a bypass valve 188 is opened to allowsubstitution fluid to flow via a conduit 189 which leads to a dialysateoutlet port 52 of dialysate compartment 46 of dialyzer cartridge 23.

First sterile filter cartridge 11 contains a semi-permeable membrane 14that separates the filter cartridge into an upstream compartment 49 anda downstream compartment 5. Upstream compartment 49 has an inlet port 56and an outlet port 54, the latter being connected to a conduit 19. Airmaybe vented from upstream compartment 49, via outlet port 54 andconduit 19 upon opening of a valves 130 and a valve 29. Closing of valve130 forces the dialysate fluid to filter (or permeate) acrosssemi-permeable membrane 14 and into downstream compartment 5.

The filtrate from downstream compartment 5 then flows into secondsterile filter cartridge 13 containing a semi-permeable membrane 15which separates the filter cartridge into an upstream compartment 50 anda downstream compartment 51. Upstream compartment 50 has an outlet port55 for venting air from both compartment 5 of cartridge 11 andcompartment 50 of cartridge 13. Outlet port 55 is connected to a conduit20 which is connected to the venting line between valves 130 and 29.Closing of both valves 29 and 130 forces the dialysate to filter acrosssemi-permeable membrane 15 and into downstream compartment 51. Thefiltered dialysate flows out of compartment 51 and through a check valve134, which minimizes blood back-flow into sterile filter cartridge 13.

The sterile dialysate (or substitution fluid) 16 exiting sterile filtercartridge 13 is mixed with blood exiting cartridge 23 to form theblood/substitution fluid mixture 17 described above. In some embodimentsof the present invention (not shown in the drawings), a portion ofsubstitution fluid may be added to the blood stream exiting seconddialyzer cartridge 22, provided that the blood does not become overlyviscous in the second dialyzer cartridge due to hemoconcentration.

During priming or flushing of sterile filter cartridges 11 and 13,valves 130 and 29 are opened to allow flow therethrough. The flowdownstream of valve 29 is directed, via a suitable fluid conduit, to ajunction near dialysate outlet port 52 of dialyzer cartridge 23. An airdetector 124 may be placed downstream of valve 29, to ensure that air ispurged from sterile filter cartridges 11 and 13 during priming.

The dialysate not used as substitution fluid enters the second dialyzercartridge 22 through inlet port 1 of dialysate compartment 48, and flowscounter-parallel to the blood flow as it traverses through compartment48. During diafiltration, plasma water filters across semi-permeablemembrane 25 and mixes with the dialysate fluid. The dialysate fluidtogether with the filtered plasma water exits the dialyzer cartridge, atoutlet port 3, through a tubing conduit 174 which directs the fluid to afirst path, including a bypass valve 131, and a second path including apump 120. Downstream of valve 131 and pump 120, the two paths arerejoined and the combined fluid flow is connected to an inlet port 4 ofdialysate compartment 46 of first dialyzer cartridge 23.

In an embodiment of the present invention, to raise the dialysate flowrate into first dialyzer cartridge 22, an additional flow of water 164may be added to the dialysate flow stream downstream of pump 120. Theaddition of water flow 164 into the dialysate flow stream raises thedialysate flow rate and increases the dialysate concentration gradientin dialyzer cartridge 23. The non-isosmotic nature of the dialysate maycause a fluid shift across red cell membranes in the treated blood,thereby improving the removal of solutes from the blood.

Pressure transducers 123 and 122 monitor pre-pumping and post-pumpingpressures, respectively, across pump 120, and inputs responsive to thesepressures are provided to control unit 40. A flow switch 34 and aconductivity meter 185 may be placed on the line leading to dialysateinlet port 4. Flow switch 34 may be used to ensure that a minimumdialysate flow is maintained to carry out the diafiltration operation.The output of conductivity meter 185 may be used to ensure that theconductivity of the dialysate is maintained within a predetermined,acceptable range, for example, a conductivity range which yields a finaldialysate sodium concentration (i.e., concentration after dilution withwater) of about 70 meq/L to about 135 meq/L. Based on the output ofconductivity meter 185, if the dialysate conductivity falls outside theacceptable range, opening of a bypass valve 186 directs the dialysatefluid to bypasses first dialyzer cartridge 23 via a bypass conduit 190.

During normal operation of the system, valve 131 is closed whereby allflow is diverted to pump 120. In this mode, the speed of the pump can beused to control the amount of ultrafiltration that occurs across thesecond dialyzer cartridge membrane 25. For example, if the rate of fluidflow pumped by pump 120 matches the inlet dialysate flow rate intocompartment 48, then the net ultrafiltration of fluid across themembrane is zero. Increasing the speed of the pump to pump above theinlet dialysate flow rate results in an ultrafiltration rate equal tothe difference between these two flow rates. Dialysate fluid enteringfirst dialyzer cartridge 23 through inlet port 4 runs counter-parallelto the blood flow as it traverses through the dialysate compartment 46.Plasma water filters across semi-permeable membrane 24 of cartridge 23into compartment 46, where the plasma water is combined with thedialysate fluid, and the combined fluid exits at dialysate outlet port52.

The used dialysate fluid may be returned to primary balancing module 158via a dialysate outlet line connector 38, connected to dialysate outletport 52 of dialyzer cartridge 23, and a conduit 42. A conduit 165carries the used dialysate from dialysate outlet connector 38 to an airtrap 166. In the air trap, air is removed via a conduit 196 which leadsto a drain 176. The resultant air-free, used, dialysate fluid flowsthrough a conduit 167 where it branches to a main dialysate pump 169and, via a conduit 168, to a secondary dialysate pump 170. Maindialysate pump 169 feeds used dialysate fluid, via a blood leak detector173 and conduit 42, back to main balancing module 158. The useddialysate exits main balancing module 158 via a conduit 175 which leadsto drain 176. A heat exchanger (not shown in the drawing) may be used topartially heat the incoming water, thereby to assist the heatingfunction of water preparation module 151.

The used dialysate fluid not entering main balancing module 158 ispumped by secondary pump 170 via a conduit 168 to a secondary balancingmodule 160, which may include a fluid balancing chamber as is known inthe art. The purpose of second balancing module 160 is to ensure thatany additional flow of water into the dialysate fluid circuit and/orinto the substitution fluid circuit, i.e., into the non-isosmoticportions of system, is balanced by a substantially equivalent removal ofused dialysate fluid from those non-isosmotic circuits. The useddialysate from secondary balancing module 160 exits via a conduit 172which leads to drain. The flow of this exiting stream is matched by theentering flow of fresh water from the water preparation module 151 viaconduit 153, pump 159 and conduit 161. Fresh water 162 exiting secondarybalancing module 160 branches into two water streams, namely a stream177 which feeds water to pump 163, leading to the substitution fluidcircuit, and a stream 164 which feeds water to the dialysate fluidcircuit.

It will be appreciated by persons skilled in the art that the use of twodialyzer stages, as described above, enables increased dialysate flowinto the first dialyzer and, thus, increased solute clearance in thefirst dialyzer, without increasing the cost normally associated withincreased dialysate flow. This is achieved by using a substantiallyhypotonic dialysate in the first dialyzer stage and a substantiallyisotonic dialysate or slightly hypertonic in the second dialyzer stage.Isotonic or slightly hypertonic dialysate is introduced only in thesecond dialyzer stage to bring the substantially hypotonic blood exitingthe first dialyzer stage to a desired range of isotonicity, therebyreducing the amount of isotonic dialysate used. The hypotonic dialysateused in the first stage is less expensive than the isotonic dialysateused in the second stage because the hypotonic dialysate is more diluted(i.e., contains less salts per unit volume) than isotonic dialysate. Thediluted dialysate used in the first stage operates to remove salts fromthe blood, and these salts are replaced by salts from the moreconcentrated dialysate used in the second stage.

Reference is now made also to FIG. 2 which schematically illustrates anembodiment of control unit 40. Control unit 40 may include a processor220 which monitors and controls the operation the hemodiafiltrationsystem. As shown more specifically in FIG. 1, control unit 40 receivesinputs from various components of the hemodiafiltration device, e.g.,from pressure transducers, flow meters, conductivity meters, flowswitches, etc., as described above. These inputs may be processed bysensor signal processing circuits 200, which may includeanalog-to-digital (D/A) converters and other circuits as are known inthe art, providing an input which is readable by processor 220. Usingsuitable control hardware and/or software, for example, device actuatorcircuits 230 as shown in FIG. 2, control unit 40 controls various systemfunctions, such as setting values for pump speeds, opening/closingvalves. Various system parameters, calculated based on the inputs may bedisplayed on a display 210 of control unit 40.

While certain specific embodiments of the invention are disclosed astypical, the invention is not limited to these particular forms, butrather is applicable broadly to all such variations as fall within thescope of the appended claims. To those skilled in the art to which theinvention pertains many modifications and adaptations will occur. Thus,the specific structures and methods discussed in detail above are merelyillustrative of specific embodiments of the invention.

What is claimed is:
 1. In a blood cleansing system, a hemodiafiltrationdevice comprising: a first dialyzer including: a first semi-permeablemembrane partitioning said first dialyzer into: a first bloodcompartment having a first blood inlet which receives blood to becleaned and a first blood outlet which discharges at least partiallydiafiltered blood, the blood received within the first blood inlet beingin an isosmotic state; and a first dialysate compartment having a firstdialysate inlet and a first dialysate outlet; a second dialyzerincluding: a second semi-permeable membrane partitioning said seconddialyzer into: a second blood compartment having a second blood inletreceives the partially diafiltered blood and a second blood outlet whichdischarges diafiltered blood; a second dialysate compartment having asecond dialysate inlet and a second dialysate outlet; and a firstdialysate fluid supply which supplies a first non-isosmotic dialysatefluid through a first conduit to the first dialysate inlet of said firstdialyzer causing the blood discharged from the first blood outlet to bein a non-isosmotic state, and a second dialysate fluid supply whichsupplies a second dialysate fluid through a second conduit to the seconddialysate inlet of said second dialyzer, the second dialysate fluidhaving an osmolarity opposite that of the first non-isosmotic dialysatefluid so that the blood being discharged from the second blood outlet isreturned substantially to the isosmotic state.
 2. A hemodiafiltrationdevice according to claim 1 wherein each of said first and seconddialysate fluid supplies comprises: a water preparation module whichprovides a supply of water; a source of dialysate fluid concentrate; anda dialysate fluid preparation module which mixes said supply of waterwith a predetermined amount of dialysate fluid concentrate to produceone of said first and second dialysate fluids.
 3. A hemodiafiltrationdevice according to claim 1 wherein said first non-isosmotic dialysatefluid comprises hypotonic dialysate fluid.
 4. A hemodiafiltration deviceaccording to claim 1 wherein said first non-isosmotic dialysate fluidcomprises hypertonic dialysate fluid.
 5. In a blood cleansing system, ahemodiafiltration device comprising: a first dialyzer including: a firstsemi-permeable membrane partitioning said first dialyzer into: a firstblood compartment having a first blood inlet which receives blood to becleaned and a first blood outlet which expels partially diafilteredblood; and a first dialysate compartment having a first dialysate inletand a first dialysate outlet; means for mixing said partiallydiafiltered blood with substitution fluid from a source of substitutionfluid to obtain a blood/substitution fluid mixture; a second dialyzerincluding: a second semi-permeable membrane partitioning said seconddialyzer into: a second blood compartment having a second blood inletwhich receives said blood/substitution fluid mixture and a second bloodoutlet which expels diafiltered blood; and a second dialysatecompartment having a second dialysate inlet and a second dialysateoutlet; a first dialysate fluid supply which supplies non-isosmoticdialysate fluid through a conduit to said first dialysate inlet; asecond dialysate fluid supply which supplies a second dialysate fluidthrough a conduit to said second dialysate inlet; and a control unitwhich controls the flow of blood through said first and second dialyzersand the flow of dialysate fluid through said first and second dialysatecompartments.
 6. A hemodiafiltration device according to claim 5 whereinsaid first and second dialyzers comprise first and second cartridges,respectively.
 7. A hemodiafiltration device according to claim 5 whereinsaid non-isosmotic dialysate fluid comprises hypotonic dialysate fluid.8. A hemodiafiltration device according to claim 5 wherein saidnon-isosmotic dialysate fluid comprises hypertonic dialysate fluid.
 9. Amethod of hemodiafiltration comprising the steps of: supplying a bloodinflow; diafiltering said blood inflow using a first non-isosmoticdialysate fluid to provide a partially diafiltered blood outflow; mixingsaid partially diafiltered blood outflow with a substitution fluid toprovide a blood/substitution fluid mixture; and diafiltering saidblood/substitution fluid mixture using a second non-isosmotic dialysatefluid.
 10. A method according to claim 9 wherein the step ofdiafiltering said blood inflow comprises the step of diffusing a portionof said blood inflow into a countercurrent of said first non-isosmoticdialysate fluid, and wherein the step of diafiltering saidblood/substitution fluid mixture comprises the step of diffusing aportion of said blood/substitution fluid mixture by a countercurrent ofsaid second non-isosmotic dialysate fluid.
 11. A method according toclaim 9 wherein the first non-isosmotic dialysate fluid comprises ahypotonic dialysate fluid and wherein said second non-isosmoticdialysate fluid comprises a hypertonic dialysate fluid.
 12. A methodaccording to claim 9 wherein said first non-isosmostic fluid comprises ahypertonic dialysate fluid and wherein said second non-isosmoticdialysate fluid comprises a hypotonic dialysate fluid.
 13. A methodaccording to claim 10 wherein said first non-isosmotic dialysate fluidcomprises a hypotonic dialysate fluid and wherein said secondnon-isosmotic dialysate fluid comprises a hypertonic dialysate fluid.14. A method according to claim 10 wherein said first non-isosmoticdialysate fluid comprises a hypertonic dialysate fluid and wherein saidsecond non-isosmotic dialysate fluid comprises a hypotonic dialysatefluid.
 15. In a blood cleansing system, a hemodiafiltration devicecomprising: a first dialyzer including: a first semi-permeable membranepartitioning said first dialyzer into a first blood compartment and afirst dialysate compartment, said first blood compartment having a firstblood inlet for receiving blood to be cleaned and a first blood outletfor discharging blood having a first concentration of toxins, the bloodreceived through the first blood inlet being in an isosmotic state, saidfirst dialysate compartment having a first dialysate inlet and a firstdialysate outlet; a second dialyzer including: a second semi-permeablemembrane partitioning said second dialyzer into a second bloodcompartment and a second dialysate compartment, said second bloodcompartment having a second blood inlet for receiving the blood havingthe first concentration of toxins and a second blood outlet fordischarging blood having a second concentration of toxins, wherein thesecond concentration is less than the first concentration, said seconddialysate compartment having a second dialysate inlet and a seconddialysate outlet; a first dialysate fluid supply which supplies a firstnon-isosmotic dialysate fluid through a first conduit to said firstdialysate inlet of said first dialyzer such that the blood dischargedfrom the first blood outlet being in a non-isosmotic state; and a seconddialysate fluid supply which supplies a second dialysate fluid through asecond conduit to said second dialysate inlet of said second dialyzer,the second dialysate fluid having an osmolarity opposite that of thefirst non-isosmotic dialysate fluid so that the blood being dischargedfrom the second blood outlet is returned substantially to the isosmoticstate.
 16. A hemodiafiltration device according to claim 15 wherein saidfirst non-isosmotic dialysate fluid comprises a hypotonic dialysatefluid.
 17. A hemodiafiltration device according to claim 15 wherein saidfirst non-isosmotic dialysate fluid comprises a hypertonic dialysatefluid.
 18. A hemodiafiltration device according to claim 15 wherein eachof said first and second dialysate fluid supplies comprises: a waterpreparation module which provides a supply of water; a source ofdialysate fluid concentrate; and a dialysate fluid preparation modulewhich mixes said supply of water with a predetermined amount ofdialysate fluid concentrate to produce one of said first and seconddialysate fluids.
 19. A method of hemodiafiltration comprising the stepsof: supplying a blood inflow, the blood inflow being in an isosmoticstate; diafiltering said blood inflow with a first non-isosmoticdialysate fluid to provide a first blood outflow having a firstconcentration of toxins and being in a non-isosmotic state; anddiafiltering said first blood outflow with a second dialysate fluid toprovide a second blood outflow having a second concentration of toxins,wherein the second concentration is less than the first concentrationand wherein the second dialysate fluid has an osmolarity opposite thatof the first non-isosmotic dialysate fluid so that the blood beingdischarged from the second blood outlet is returned substantially to theisosmotic state.
 20. A method according to claim 19 wherein said firstnon-isosmotic dialysate fluid comprises a hypotonic dialysate fluid. 21.A method according to claim 19 wherein said first non-isosmoticdialysate fluid comprises a hypertonic dialysate fluid.
 22. In a bloodcleansing system, a hemodialysis device comprising: a first dialyzerincluding: a first semi-permeable membrane partitioning said firstdialyzer into a first blood compartment and a first dialysatecompartment, said first blood compartment having a first blood inlet forreceiving blood to be cleaned and a first blood outlet for dischargingblood having a first concentration of toxins, the blood received throughthe first blood inlet being in an isosmotic state, said first dialysatecompartment having a first dialysate inlet and a first dialysate outlet;a second dialyzer including: a second semi-permeable membranepartitioning said second dialyzer into a second blood compartment and asecond dialysate compartment, said second blood compartment having asecond blood inlet for receiving the blood from the first dialyzer and asecond blood outlet for discharging blood having a second concentrationof toxins, wherein the second concentration is less than the firstconcentration, said second dialysate compartment having a seconddialysate inlet and a second dialysate outlet; a first dialysate fluidsupply which supplies a first non-isosmotic dialysate fluid through afirst conduit to said first dialysate inlet of said first dialyzer suchthat the blood discharged from the first blood outlet is in anon-isosmotic state; and a second dialysate fluid supply which suppliesa second dialysate fluid through a second conduit to said seconddialysate inlet of said second dialyzer, the second dialysate fluidhaving an osmolarity opposite that of the first non-isosmotic dialysatefluid so that the blood being discharged from the second blood outlet isreturned substantially to the isosmotic state.
 23. A method ofhemodialysis comprising the steps of: supplying a blood inflow, theblood inflow being in an isosmotic state; dialyzing said blood inflowwith a first non-isosmotic dialysate fluid to provide a first bloodoutflow having a first concentrations of toxins, the first blood outflowbeing in a non-isosmotic state; and dialyzing said blood outflow fromsaid first dialyzer with a second dialysate fluid to provide a secondblood outflow having a second concentration of toxins, the secondconcentration of toxins being less than the first concentration oftoxins, the second dialysate fluid having an osmolarity opposite that ofthe first non-isosmotic dialysate fluid so that the second blood outflowis returned substantially to the isosmotic state.